Pearls
- •
Liver transplantation (LT) has become the standard of care for children with end-stage or metabolic liver disease, acute liver failure, and unresectable liver tumors, with most common indication being biliary atresia.
- •
A child’s ability to tolerate the transplant-specific physiologic demands and recover following LT are related more to pretransplant functional status and physiologic reserve than the magnitude of the transplant procedure itself.
- •
Donor liver grafts now include segmental or isolated lobe grafts, split liver grafts, living donor, and deceased after circulatory death grafts.
- •
The overarching principle guiding specific intraoperative technical decision-making is to optimize liver graft perfusion (inflow) and avoid outflow obstruction and resultant graft congestion and edema.
- •
Complications following LT occur commonly and may derive from pretransplant recipient condition, graft-specific factors (including preservation and ischemia-reperfusion injury), technical or intraoperative complications, the immunologic response to the graft, or infection.
- •
Transplant outcomes now exceed 90% patient survival at 1 year and 80% at 5 years.
Liver transplantation (LT) is now widely accepted as the standard of care for the management and treatment of acute liver failure and end-stage liver disease in children. Since the first liver transplant in a child performed by Thomas Starzl in 1963, remarkable progress has been made; children undergoing liver transplantation today should realize 5-year survival exceeding 80%. The improvement in outcomes has resulted from continuous progress across the spectrum of care of children in need of LT. Advances in diagnosis and management of liver disease, development of improved intensive care support and therapies, and refinement of transplant surgical technique and perioperative care have contributed to improved overall patient and graft survival. The recognition of the importance of nutritional support, prompt diagnosis and treatment of infection, and advances in management of the multisystem complications of both chronic liver disease and acute liver failure have contributed to improved pretransplant survival of these children and improved condition at time of transplantation. Expansion of donor liver graft options beyond the whole-organ deceased donor graft to now include segmental or isolated lobe grafts, split liver grafts, living donor, and deceased after circulatory death (DCD) grafts have greatly expanded the transplant possibilities for children on the waiting list. Changes in donor organ allocation policies and improved organ preservation allowing broader geographic distribution have also increased potential access for children to donor liver grafts. Posttransplant management has also improved, including immunosuppression, earlier recognition of rejection and infection, and earlier recognition of vascular and biliary complications, all of which have contributed to improved outcomes. While the primary indication and role of LT is to increase survival in patients with life-limiting acute or chronic liver conditions, the overall excellent survival outcomes realized today have allowed for expanded consideration of LT in certain clinical situations to improve quality of life of children suffering debilitating complications or side effects related to their liver disease.
Current state of pediatric liver transplantation
In 2018, approximately 525 children were registered on the United Network for Organ Sharing (UNOS) national liver transplant wait list, more than half of whom were aged 5 years or younger. During the year, 700 children were added to the wait list and 563 LTs were performed; 62 were living donor transplants. A trend toward increased medical urgency, evidenced by an increased proportion of Status 1A and 1B listings, has continued over the past several years. The increasing acuity at transplantation is reflected in higher utilization of split liver transplants, which comprised 19.2% of pediatric liver transplants performed, as compared with 14.4% in 2008. This contrasts to the static 1% proportion of split liver grafts performed in adults over the same period. The utilization of living donor LT also continues to expand, representing 11% of transplantations performed in 2018. Together, the increased use of split liver and living donor transplant and high acuity at operation reflect overall limited access to suitable donor organs for children on the wait list. Despite these efforts to increase transplant opportunity for children, approximately 4.3% of children died on the wait list, and another 2.7% were removed from the list because they had become too sick to benefit from operation. The wait list mortality was highest in children younger than 1 year who had a death rate of 17.1 deaths per 100 wait list–years. This pretransplant mortality risk is highest of all age groups awaiting a lifesaving LT.
Indications for liver transplant
Liver transplantation is indicated for irreversible liver failure, life-threatening complications of underlying liver disease, or secondary organ complications resulting from the liver disease. Primary liver disease or condition-specific indications fall into four broad categories: chronic liver disease, acute liver failure, metabolic liver disease, and unresectable liver tumors ( Box 97.1 ). Other disorders, many of which are newer indications, include cystic fibrosis liver disease, nonfatal metabolic liver disease, and portosystemic shunts.
End-stage liver disease
Cholestatic liver disease
Biliary atresia
Alagille syndrome
Progressive familial intrahepatic cholestasis
Primary sclerosing cholangitis
Disorders of bile acid synthesis
Chronic hepatitis
Viral hepatitis
Autoimmune hepatitis
Cryptogenic cirrhosis
Metabolic liver disease
α 1 Antitrypsin deficiency
Urea cycle defects
Tyrosinemia
Glycogen storage disease
Wilson disease
Cholesterol ester storage disease
Crigler-Najjar type 1
Organic acidemias
Primary oxalosis
Acute liver failure
Fulminant viral hepatitis
Autoimmune hepatitis
Acetaminophen-induced hepatic necrosis
Toxin-induced hepatic necrosis
Wilson disease
Liver tumor
Unresectable malignancy
Hepatoblastoma
Hepatocellular carcinoma
Benign liver tumor
Hemangioendothelioma
Retransplantation
Hepatic artery thrombosis
Primary graft nonfunction
Ischemic cholangiopathy
Chronic rejection
Miscellaneous
Cystic fibrosis
Neonatal iron storage disease
Drug toxicity
Polycystic liver disease
Hepatopulmonary syndrome
Parenteral nutrition–associated liver disease
Caroli disease
Liver insufficiency postresection or injury
The most common indication for LT in children is biliary atresia, followed by metabolic and inborn disorders, autoimmune and familial cholestatic disorders, and acute hepatic necrosis. Unresectable malignancy accounts for approximately 5%, and retransplantation now comprises slightly less than 10% of pediatric LT performed annually.
Biliary atresia is a progressive fibro-obliterative disease of early infancy that results in biliary obstruction and fibrosis and can progress to biliary cirrhosis despite performance of a Kasai portoenterostomy. Despite a high rate of progression of liver disease, approximately two-thirds of infants will clear their jaundice following the Kasai portoenterostomy, delaying the need for early LT and permitting time for growth. Children with biliary atresia represent approximately 45% of pediatric LT, with the majority requiring a transplant before age 2 years. These infants typically present with jaundice, coagulopathy, or poor growth. They may also develop episodes of cholangitis, or bacterial peritonitis. Hepatic cirrhosis is often associated with portal hypertension, hepatosplenomegaly, and ascites. Nutritional failure and hypersplenism contribute to increased risk for bleeding and infection. In addition to the liver disease, approximately 15% of infants with biliary atresia have associated congenital malformations that may include polysplenia or asplenia, interrupted inferior vena cava, preduodenal portal vein, and situs inversus (biliary atresia splenic malformation). These anatomic malformations may specifically impact technical aspects and decisions of the liver transplant procedure, limiting options for suitable donor liver grafts in this select group of biliary atresia patients.
Metabolic liver diseases include a spectrum of clinical presentations and urgency and result from a single hepatic enzyme deficiency that leads to alteration in synthesis, transport, function, or breakdown of carbohydrate, fat, or protein. Some metabolic disorders may be associated with progressive liver disease and cirrhosis (e.g., α 1 -antitrypsin deficiency, Wilson disease, progressive familial intrahepatic cholestasis), or malignancy (e.g., tyrosinemia). Other inborn errors of metabolism are characterized by absence of hepatocellular injury but result in extrahepatic organ injury or dysfunction due to failure of normal hepatic enzyme function. Urea cycle defects cause abnormal protein breakdown, resulting in hyperammonemia, which can cause significant neurologic injury and impair development. Hyperoxaluria type 1 manifests with renal complications, and hypercholesterolemia or disorders of iron metabolism can cause serious cardiac complications. Clinical presentation of metabolic liver disease may range from the newborn period (extreme hyperammonemia due to urea cycle defect) to adolescence and into adulthood (e.g., Crigler-Nijjar, Wilson disease). The urgency of LT is related to risk of severe or life-altering complications of the specific metabolic defect, and the effectiveness of alternative supportive therapies.
Although many children recover from acute liver failure with supportive intensive care management, renal replacement therapy, and liver-specific support in nutrition and coagulation, those with overwhelming hepatocyte necrosis may develop extreme hypoglycemia, progressive encephalopathy, and coagulopathy refractory to supportive measures. Life-threatening extrahepatic complications—including cerebral edema with intracranial hypertension and coma, renal failure due to hepatorenal syndrome, and pulmonary hypertension—may develop and are associated with high mortality without urgent LT.
Of the primary liver tumors of childhood, hepatoblastoma is the most common, often presenting with a large primary liver mass during infancy. Greater than one-third are unresectable at presentation, and many have pulmonary metastases at presentation. Despite good response to neoadjuvant chemotherapy, approximately 10% of these large tumors will remain unresectable. The achievement of a satisfactory oncologic resection—including complete removal of the tumor with negative histologic margins while providing sufficient remnant liver volume for adequate liver function—may not be possible in cases of large tumors. Total hepatectomy and liver transplant is indicated in those cases. Hepatocellular carcinoma (HCC), the second most common liver malignancy, typically occurs in older children and adolescents. In contradistinction from its association with chronic viral hepatitis in adults, HCC in children typically arises in an otherwise normal liver and presents as a large unresectable tumor. Despite the advanced clinical status at presentation, long-term survival outcomes following liver transplant now exceed 80%, approaching those of nonmalignant diagnoses.
Combined liver-intestine transplantation is indicated in the context of irreversible parenteral nutrition–associated liver disease in children with intestinal failure and short-bowel syndrome. Liver-kidney transplantation in children is primarily indicated in metabolic liver disease resulting in renal failure, such as hyperoxaluria or methylmalonic academia. Unlike in adults, combined liver-kidney transplantation for hepatorenal syndrome in children is rarely performed, and renal recovery often follows liver transplantation alone.
With improvements in overall survival outcomes plus greater awareness and management of transplant complications contributing to lower early morbidity, LT is now appropriately indicated to improve quality of life in children with liver disease–associated complications such as intractable pruritus or poor growth and development. Contraindications to LT include uncontrolled systemic infection, presence of uncontrolled extrahepatic malignancy, or progressive life-limiting extrahepatic disease or condition.
Liver transplant evaluation
The goals of transplant evaluation are to identify anatomic and functional data necessary to perform the LT procedure safely while also identifying other medical, social, or infection history that must be managed in order to achieve a successful outcome. Liver transplant evaluation typically includes laboratory tests to determine ABO blood type, complete blood count, electrolytes, and renal and hepatic synthetic function studies. Virology studies to identify past infection or vaccination for hepatitis A, B, and C or human immunodeficiency virus in addition to serologies for cytomegalovirus (CMV) or Epstein-Barr virus (EBV) aid in managing immunosuppression and infection prophylaxis posttransplant. Doppler ultrasound (US) of the liver and computed tomography of the abdomen provide information regarding vascular anatomy and patency or thrombosis of portal venous inflow and allow assessment of size and space considerations for potential donor grafts. Echocardiography is obtained to assess cardiac anatomy and function, especially to identify preexisting pulmonary hypertension or atrial or ventricular enlargement or dysfunction. Social work and/or a psychological evaluation aid in assessing patient and family support challenges to adherence with recommended care and psychosocial issues that may require specific support, including financial or housing assistance in anticipation of hospitalization related to the transplant.
Patient and family education regarding pre-, peri-, and postoperative stages of the transplant process is a key component of LT evaluation. General information regarding the transplant system in the United States specifically in the geographic region of the transplant center and the process of prioritization and allocation of donor organs to patients on the wait list must be discussed. Donor options (including whole-organ, live donor, and deceased donor grafts) and technical variant grafts (including reduced lobar or segmental liver grafts) are reviewed along with specific complications that may be associated with each different donor graft type. A thorough discussion of risk of posttransplant infection specifically relating to immunosuppression and risk for viral infections—particularly EBV and CMV—should be included. Additionally, education should address potential donor-transmitted infections plus procedures and protocols to monitor and manage them if they occur. Alternatives to transplant should also be discussed to ensure that LT is the most appropriate course.
Pretransplant considerations
The ideal management of a child awaiting LT should focus on optimizing overall health. The child’s ability to tolerate the transplant-specific physiologic demands and recover following LT are related more to pretransplant functional status and physiologic reserve than to the magnitude of the transplant procedure itself. Therefore, it is critical to actively monitor and promptly manage complications of advancing liver disease, portal hypertension, variceal bleeding, and any intercurrent illnesses. Children with advancing liver disease often require nutritional support or treatment of infection. Supplemental enteral feedings or parenteral nutrition may be used to provide optimal calorie and protein intake. Diuretic management and fat-soluble vitamin repletion are commonly required, indicating progressing portal hypertension and liver dysfunction. Decreased muscle mass, fatigue, and abdominal distension due to hepatosplenomegaly or ascites may contribute to restrictive pulmonary physiology or increased work of breathing, further demonstrating the importance of adequate caloric intake.
Another essential goal of the preoperative period is to optimize the child’s transplant priority on the wait list itself, which is determined by clinical urgency of the recipient and the severity of liver disease. Systems to prioritize candidates waiting for LT differ in various countries. In the United States, UNOS administers the Organ Procurement and Transplantation Network, which matches donors with recipients. Children with acute liver failure qualify for most urgent listing, Status 1A. Children with chronic liver disease or malignancy who experience life-threatening complications may qualify for Status 1B. Children under 12 years of age on the wait list are prioritized according to a calculated Pediatric End-Stage Liver Disease (PELD) score, which incorporates values for bilirubin, albumin, and international normalized ratio (INR). In young infants, growth failure and age less than 1 year also contribute to the PELD calculation. The PELD score will ideally stratify children according to their 3-month liver disease–related mortality risk, with higher scores indicating greater risk of dying without transplant. Adolescents and adults are prioritized according to a calculated Model for End-Stage Liver Disease (MELD) score, which incorporates bilirubin, INR, and creatinine. In specific cases in which the calculated PELD score does not accurately represent the severity of liver disease and associated mortality risk, centers may request a higher PELD exception score, which is reviewed by a national review board. Active management of children on the wait list and frequent reassessment of listing priority are strategies shown to be associated with higher transplant rates and lower wait list mortality.
Transplant considerations
Donor considerations
Evaluation of potential donors for LT includes assessment of liver function; screening for donor medical history for disease, malignancy, and infection; ABO blood typing; and general size-matching with the intended recipient. Deceased donors may meet criteria for death by neurologic criteria (brain death) or may have suffered extreme injury and qualify as donors after withdrawal of life support therapy (DCD; see Chapter 20 ). Organ donation proceeds after declaration of circulatory death; these DCD organs experience a period of warm ischemia after withdrawal of support and before circulatory death.
Donors for pediatric LT tend to be young and free of preexisting disease. This may allow for size-matched whole-organ transplant or enable the use of technical variant grafts, including segmental or lobar grafts. A donor liver may be divided in situ (during the donor operation) or ex situ (on the backbench after recovery of whole liver). Liver reduction may produce a single, smaller-sized graft, or split, divided to result in two separate transplantable grafts. The use of technical variant grafts has resulted in shorter waiting times and decreased wait list mortality for small children and infants in need of LT, though it has been associated with increased incidence of vascular and biliary complications when compared with whole-organ transplants but equivalent survival.
Living donor transplantation has been an excellent option since first introduced in the 1980s. The most common living donor graft for children is the left lateral segment graft, most often used in transplantation in infants. Living donor LT allows better planning with elective, optimally earlier, timing for transplant. While living donor transplant operations have increased operative and logistic complexity, recent reports demonstrate superior short- and long-term graft and patient survival following living donor LT compared with deceased donor transplantation.
Determination of best donor option for a child awaiting LT requires complex, dynamic decision-making, largely dependent on the availability of donor offers or potential living donor and the patient’s clinical status. In the stable child with a chronic liver condition, it may be appropriate to await a size-matched, ABO-identical donor liver offer with anticipated short ischemia time. For children in the ICU, requiring advance support, or with acute liver failure, waiting for such a restricted donor offer would unduly increase the risk of dying before a suitable donor becomes available. In such urgent situations, expanding donor options to include ABO-incompatible grafts and technical variant reduced grafts, such as monosegment grafts; using DCD or donors with increased risk for disease transmission; extending the geographic range; and accepting longer ischemia time can enable transplantation and can be lifesaving.
Liver transplant procedure
The LT operation involves the removal of the native organ with preservation or creation of the inferior vena cava (IVC) outflow and hepatic arterial and portal vein inflow. The donor graft is placed in the same position as the native liver. Typically, three vascular anastomoses and one biliary anastomosis are required. The overarching principle guiding specific intraoperative technical decision-making is to optimize liver graft perfusion (inflow) and avoid outflow obstruction and resultant graft congestion and edema.
The donor whole-liver suprahepatic IVC or segmental graft hepatic vein is anastomosed to the recipient IVC to establish venous outflow as the first step in implanting the liver graft. The recipient retrohepatic vena cava may be preserved during the native hepatectomy, enabling a “piggyback” technique with venous anastomosis to the front of the IVC. Portal vein anastomosis to establish inflow to the graft and restore mesenteric venous drainage from the small intestine and spleen is then performed. Care is taken to identify and ligate preexisting portosystemic shunts that may compete with and compromise portal vein flow to the graft. Reperfusion of the liver graft typically follows as the clamps are released, restoring portal inflow and hepatic venous outflow. Hepatic artery inflow is then established after reperfusion, with anastomosis to the recipient hepatic or celiac artery. If inadequate portal vein or hepatic artery flow is found, vascular grafts may be extended to the superior mesenteric vein or aorta to improve inflow. This sequence of vascular anastomoses is possible because of the dual blood supply to the liver (portal vein and hepatic artery) and also enables shorter graft ischemia time. Technical variations may include creation of a temporary portocaval shunt to maintain mesenteric venous outflow and minimize splanchnic congestion during the anhepatic phase.
Biliary drainage is accomplished by duct-to-duct anastomosis or donor bile duct to roux-en-Y anastomosis. Primary liver disease, type of donor liver graft, and donor-recipient size mismatch are considered in determining best biliary drainage. In children with biliary atresia, the roux-en-Y limb created for Kasai portoenterostomy typically serves for graft bile duct anastomosis.
Preexisting portal hypertension, adhesions related to previous abdominal surgery, and coagulopathy due to synthetic liver dysfunction contribute to risk for bleeding both intraoperatively and in the early postoperative period. Ascites and prior episodes of cholangitis or intraperitoneal infection also contribute to this operative risk. With significant donor-recipient size discrepancy or edema of graft, intestine or abdominal wall, primary abdominal closure may be delayed and a temporary patch closure employed to avoid impairment of liver graft blood flow or abdominal compartment syndrome.
Complications of liver transplantation
Complications following LT occur commonly and may derive from pretransplant recipient condition; graft-specific factors, including preservation and ischemia-reperfusion injury; technical or intraoperative complications; the immunologic response to the graft; or infection. Technical complications encountered early in the posttransplant period include vascular and biliary complications, intraabdominal bleeding, and wound complications. Organ dysfunction, infection, or rejection generally develop weeks after transplantation. Immunosuppression toxicity may manifest at any time.
Primary graft nonfunction
Primary nonfunction (PNF) of the graft is a rare, but potentially devastating, complication characterized by severe hepatic dysfunction in the absence of vascular thrombosis. The etiology of PNF is thought to be related to graft ischemia-reperfusion injury, poor graft preservation, or prolonged cold ischemia time. Risk factors include steatosis, extremes of donor age, and DCD donor graft. PNF may lead to early graft failure and require urgent retransplantation.
Vascular complications
Vascular complications following liver transplantation include stenosis or thrombosis of the hepatic artery portal vein or hepatic vein. Routine bedside postoperative color Doppler US is indicated to assess vascular patency. Vascular thrombosis is the leading cause of graft loss requiring retransplantation among patients in the Society of Pediatric Liver Transplantation (SPLIT) Registry, with hepatic artery thrombosis accounting for 52.3% and other vascular thromboses comprising 13.8%. Stenosis may occur at the level of the anastomosis or relate to vascular dissection during organ recovery in the donor or from rotational malalignment of the donor and recipient vessels at time of anastomosis. Typically, these complications occur early in the postoperative period and may present with laboratory or clinical signs of graft dysfunction or may be detected by Doppler US. Intervention may include operative revision or repair, interventional radiology angioplasty, stent placement, or possibly retransplantation.
Hepatic artery thrombosis (HAT) is the most common vascular complication and an independent risk factor for graft loss and mortality. In the SPLIT Registry, 6.3% of patients developed HAT in the first 30 days. Three distinct clinical presentations can arise: (1) acute necrosis resulting in hepatic infarction and primary graft failure; (2) ischemic cholangiopathy, presenting early as bile leak, biliary stricture, and abscess/bacteremia; and (3) asymptomatic without graft injury. Risk factors include young age, low weight (incidence is greatest in patients <10 kg), the use of vascular grafts, and hypercoagulable conditions. HAT can present with absent or diminished arterial flow or with abnormally low resistive indices on Doppler US. When discovered in the immediate posttransplant period, HAT is an indication for emergent reexploration with thrombectomy or thrombolysis and revision. Therapeutic anticoagulation should be initiated. Even with restoration of good arterial flow, biliary stricture or hepatic necrosis may result.
Portal vein thrombosis (PVT) occurs in fewer than 5% of pediatric patients but can prove to be devastating to the graft if it occurs within the first few days after LT. The primary risk factors for PVT include pretransplant PVT or diminished portal venous flow due to established portosystemic varices that compete for mesenteric venous drainage. Incidence of PVT also increases with technical variant grafts, including reduced and split segmental grafts. Late presentation of PVT or portal vein stenosis is characterized by portal hypertension and ascites. The onset of new or increasing ascites and portal hypertension in the weeks following liver transplantation should raise concern for hepatic venous outflow obstruction. Hepatic vein stenosis may be seen in the early or delayed posttransplant period, often producing liver graft congestion, high abdominal drain output, and portal hypertension. This complication most frequently occurs in association with technical variant grafts due to rotational or compression-related issues of the graft, resulting in venous outflow obstruction. The resulting graft congestion can cause bleeding from a cut surface of segmental graft or further compromise graft inflow and cause portal hypertension.
Bleeding
Since hepatic synthetic function includes both pro- and antithrombotic proteins, patients are vulnerable to both bleeding and thrombosis. Regardless, intraoperative blood loss requiring blood product transfusion often occurs. Postoperative bleeding has been associated with worsening degrees of thrombocytopenia and hypofibrinogenemia. Blood component transfusion should be considered when patients experience hemorrhage. However, hyperviscosity and aggressive correction of coagulopathy and thrombocytopenia should be avoided to limit the potential contribution to vascular thrombosis.
Biliary complications
Biliary complications are the most frequent surgical complication of LT, occurring in approximately 15% to 20% of cases. These complications may occur early or late after transplantation; thus, they should be considered in the evaluation of any posttransplant liver dysfunction. The graft bile duct is sensitive to ischemic injury and particularly dependent on hepatic arterial inflow for perfusion. Biliary complications may present as bile leak and can be complicated by abscess or biloma. Biliary strictures that develop are a risk factor for biliary obstruction and cholangitis. HAT-related biliary strictures classically involve large, centrally located ducts, though they may also be multifocal, typically involving duct branch points. Ischemic cholangiopathy results in diffuse bile duct injury of large and small ducts and can be associated with severe ischemia-reperfusion injury or with DCD donor grafts that experience long ischemia time. Initial management for biliary strictures includes percutaneous transhepatic catheter placement in interventional radiology with drainage of intraabdominal abscess or biloma. However, surgical exploration, repair, and possible retransplantation may ultimately prove necessary.
Rejection
Acute cellular rejection is the most common complication following LT and is defined as graft injury caused by recipient immune response infiltrating the graft. Data from the SPLIT Registry suggest that acute cellular rejection occurs in nearly 35% of patients in the first year following transplantation with the highest incidence in the first 3 months. Children with acute rejection often remain asymptomatic; diagnosis is suspected based on abnormal liver function studies. The diagnosis of rejection is confirmed on liver biopsy ( Fig. 97.1 ). Episodes of acute rejection often respond completely to treatment with short courses of high-dose corticosteroid therapy and rarely lead to graft loss.
